Potential of GABAB Receptor Positive Allosteric Modulators in the Treatment of Alcohol Use Disorder

Abstract

The orthosteric γ-aminobutyric acidB (GABAB) receptor agonist baclofen is currently considered a therapeutic option for alcohol use disorder (AUD); however, the safety profile of baclofen is a concern, thus arousing interest in the positive allosteric modulators (PAMs) of the GABAB receptor (GABAB PAMs), a new class of ligands expected to possess a better safety profile. The present paper summarizes the several lines of experimental evidence indicating the ability of GABAB PAMs to inhibit multiple alcohol-motivated behaviors in rodents. All GABAB PAMs tested to date have invariably been reported to reduce, or even suppress, excessive alcohol drinking, relapse- and binge-like drinking, operant oral alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced locomotor stimulation and conditioned place preference in rats and mice. The use of validated animal models of several aspects of AUD confers translational value to these findings. The reducing effects of GABAB PAMs on alcohol-motivated behaviors (1) occurred at doses largely lower than those inducing sedation, suggesting that GABAB PAMs may possess, if compared with baclofen, a higher therapeutic index and a more favorable safety profile, and (2) were often not associated with reductions on other non-drug consummatory behaviors. Additional findings with therapeutic potential were (1) the lack of tolerance, after repeated treatment, to the reducing effect of GABAB PAMs on alcohol drinking and self-administration; (2) the efficacy of GABAB PAMs after intragastric administration; and (3) the ability of GABAB PAMs to selectively potentiate the suppressing effect of baclofen on alcohol self-administration. The recent transition of the first GABAB PAMs to the initial steps of clinical testing makes investigation of the efficacy of GABAB PAMs in AUD patients a feasible option.

Notes

Acknowledgements

The authors are grateful to Professor Federico Corelli for drawing Fig. 1, and Ms. Anne Farmer for language editing of this manuscript.

Compliance with Ethical Standards

Funding

The authors did not receive any specific grants for writing this paper.

Conflict of interest

Paola Maccioni and Giancarlo Colombo declare that they have no conflicts of interest relevant to the contents of this article.

Research involving animals

Data depicted in Fig. 1 were collected in an experiment that fully complied with European Directive no. 2010/63/EU and subsequent Italian Legislative Decree no. 26, 4 March 2014, on the ‘Protection of Animals Used for Scientific Purposes’.

Janak PH, Michael Gill T. Comparison of the effects of allopregnanolone with direct GABAergic agonists on ethanol self-administration with and without concurrently available sucrose. Alcohol. 2003;30:1–7.CrossRefPubMedGoogle Scholar